Anthracyclines of the daunorubicin group such as doxorubicin, carminomycin and aclacinomycin and their synthetic analogs are among the most widely employed agents in antitumoral therapy (F. Arcamone, Doxorubicin, Academic Press N.Y., 1981, pp. 12-25; A. Grein, Process Biochem., 16:34, 1981; T. Kaneko, Chimicaoggi May 11, 1988; C. E. Myers et al., "Biochemical mechanism of tumor cell kill" in Anthracycline and Anthracenedione-Based Anti-cancer Agents (Lown, J. W., ed.) Elsevier Amsterdam, pp. 527-569, 1988; J. W. Lown, Pharmac. Ther. 60:185-214, 1993). Anthracyclines of the daunorubicin group are naturally occurring compounds produced by various strains of Streptomyces and by Actinomyces carminata. Doxorubicin is mainly produced by strains of S. peucetius while daunorubicin is produced by many other Actinomycetes. In particular daunorubicin and doxorubicin are synthesized in Streptomyces peucetius ATCC 29050 and 27952 from malonic acid, propionic acid and glucose by the pathway summarized in Grein, Advan. Applied Microbiol. 32;203, 1987 and in Eckart and Wagner, J. Basic Microbiol. 28:137, 1988. Aklavinone (11-deoxy-.epsilon.-rhodomycinone), .epsilon.-rhodomycinone and carminomycin are established intermediates in this process. The final step in this pathway involves the hydroxylation of daunorubicin to doxorubicin, which is reported to occur only in S. peucetius species.
Daunorubicin is known to be converted to 4'-O-glycosides called baumycins in Streptomyces species (Y. Takahashi, H. Naganawa. T. Takeuchi, H. Umezawa, T. Komiyama, T. Oki and T. Inui. J. Antibiot. 30:622, 1977) thus decreasing also the amount of doxorubicin potentially obtainable through oxidation of daunorubicin. For recovering daunorubicin at the end of fermentation, baumycins are converted to daunorubicin by acid hydrolysis. However this process presents certain drawbacks in that the amount of doxorubicin thus produced is low and the process is complicated by the acid hydrolysis step. The present invention solves this problem by providing a mutated Streptomyces strain in which one of the genes responsible for the conversion of daunorubicin to baumycins has been insertionally inactivated.